New data from the phase 3b TRAILBLAZER-ALZ-6 trial indicate that an enhanced titration dosing regimen of donanemab (Kisulsa; Eli Lilly) significantly lowers the risk of amyloid-related imaging abnormalities-edema (ARIA-E) in patients with early symptomatic Alzheimer's disease (AD), while maintaining sufficient amyloid reduction. The findings, presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, suggest a potential strategy to improve the safety profile of this recently approved antiamyloid treatment.
TRAILBLAZER-ALZ-6 Trial Details
The study involved 843 adults with early symptomatic AD, stratified by apolipoprotein E (APOE) genotype and baseline amyloid levels. Participants were randomized in a 1:1:1:1 ratio to either the standard donanemab dosing arm or one of three alternative dosing arms. The primary outcome assessed the frequency of ARIA-E at 24 weeks. The four treatment arms varied in donanemab dosage per infusion and frequency of dosing, but the total donanemab exposure by week 16 was the same across all arms.
Reduced ARIA-E with Enhanced Titration
At week 24, the frequency of ARIA-E in the standard dosing arm was 23.7%. The enhanced titration dosing regimen, which exhibited the lowest ARIA-E frequency (13.7%), demonstrated a 41% reduction in the relative risk of ARIA-E compared to the standard dosing arm. Furthermore, the ARIA-E radiographic severity in the enhanced titration arm was notably less than the standard dosing arm, with a breakdown of 4.7% mild, 9.0% moderate, and 0% severe ARIA-E, compared to 9.2%, 12.6%, and 1.9%, respectively, in the standard arm. Symptomatic ARIA-E was also less frequent in the enhanced titration arm (2.8%) than in the standard dosing arm (4.8%).
Maintained Amyloid and p-tau Reduction
Importantly, donanemab's efficacy in reducing amyloid and phosphorylated tau (p-tau) was maintained with the new titrated regimen. At week 24, all arms showed significant amyloid reduction, with an adjusted mean change of -58.8 (SE, 1.8) centiloids in the standard arm and -56.3 (SE, 1.7) centiloids in the enhanced titration arm. Changes in p-tau217 levels at 24 weeks were also similar across all dosing arms.
Safety Profile
Serious adverse events, discontinuations, and treatment-related adverse events in the alternative dosing arms were generally similar to those in the standard dosing arm. However, one participant in the titration arm with ongoing ARIA-E experienced stroke-like symptoms and died from cerebral intraparenchymal hemorrhage after receiving tissue plasminogen activator. The frequency of infusion-related reactions was comparable between the alternative and standard dosing arms.
Implications for Donanemab Treatment
These findings suggest that an enhanced titration dosing regimen of donanemab could mitigate the risk of ARIA-E, a significant safety concern associated with antiamyloid therapies, without compromising the drug's efficacy in reducing amyloid plaques and p-tau. Further research is warranted to fully evaluate the long-term safety and efficacy of this modified dosing strategy.
